Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 3.9 million infected people in the United States alone, according to the U.S. Center for Disease Control, roughly five times the number of people infected with the human immunodeficiency virus (HIV). According to the World Health Organization, there are more than 170 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but about 80% of those infected harbor HCV the rest of their lives. Ten to 20% of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their off-spring.
Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. The current state of the art in the treatment of HCV infection has been discussed in the following references: Dymock et al., 2000, Antiviral Chem. & Chemotherapy 11:79-96; Rosen et al., 1999, Molec. Med. Today 5:393-399; Moradpour et al., 1999, Euro. J. Gastroenterol. Hepatol. 11:1189-1202; Bartenschlager, 1997, Intervirology 40(5-6):378-393; Lauer et al., 2001, N. Engl. J. Med. 345:41-52; Dymock, 2001, Emerging Drugs 6:13-42; and Crabb, 2001, Science 294:506-507.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein. Because it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions, the NS3 protease is considered a prime drug target. Previous research has identified classes of peptides, such as hexapeptides as well as tripeptides discussed in U.S. Patent Application Publications Nos. US2005/0020503, US2004/0229818, and US2004/00229776, showing degrees of activity in inhibiting the NS3 protease. Additional HSV NS3 protease inhibitors have been described in International Patent Application Publication Nos. WO2008/057208 and WO2008/057209. The aim of the present invention is to provide further compounds which exhibit activity against the HCV NS3 protease.